Factors associated with PrEP use in a community sample of African American men who have sex with men (MSM) and transgender women (TGW) in the United States Midwest.

Black sexual minority men who have sex with men (MSM) in the United States are at disparate risk for contracting HIV infection, but pre-exposure prophylaxis (PrEP) use is suboptimal. Social network methods were used to recruit a community sample of racial minority MSM and transgender women (TGW) in two Midwestern US cities. 250 PrEP-eligible (HIV-negative) participants completed measures assessing current and intended PrEP use; demographic characteristics; PrEP knowledge, attitudes, norms, stigma, and self-efficacy; and structural barriers to PrEP. Multivariate analyses established predictors of current and intended PrEP use. Only 12% of participants reported currently using PrEP, which was associated with greater PrEP knowledge and not having a main partner, with trends for greater PrEP use by younger participants and those with partners living with HIV. Among participants not currently on PrEP, strength of PrEP use intentions was associated with higher PrEP knowledge, PrEP descriptive social norms, and PrEP use self-efficacy. This study is among few to directly compare Black who have adopted PrEP with those who have not. Its findings underscore the potential benefits of employing social network approaches for strengthening PrEP use peer norms, increasing PrEP knowledge and self-efficacy, and optimizing PrEP uptake among racial minority MSM and TGW.

Two-Year Outcomes of Cochlear Implant Use for Children With Unilateral Hearing Loss: Benefits and Comparison to Children With Normal Hearing.

OBJECTIVES: Children with severe-to-profound unilateral hearing loss, including cases of single-sided deafness (SSD), lack access to binaural cues that support spatial hearing, such as recognizing speech in complex multisource environments and sound source localization. Listening in a monaural condition negatively impacts communication, learning, and quality of life for children with SSD. Cochlear implant (CI) use may restore binaural hearing abilities and improve outcomes as compared to alternative treatments or no treatment. This study investigated performance over 24 months of CI use in young children with SSD as compared to the better hearing ear alone and to children with bilateral normal hearing (NH). DESIGN: Eighteen children with SSD who received a CI between the ages of 3.5 and 6.5 years as part of a prospective clinical trial completed assessments of word recognition in quiet, masked sentence recognition, and sound source localization at regular intervals out to 24-month postactivation. Eighteen peers with bilateral NH, matched by age at the group level, completed the same test battery. Performance at 24-month postactivation for the SSD group was compared to the performance of the NH group. RESULTS: Children with SSD have significantly poorer speech recognition in quiet, masked sentence recognition, and localization both with and without the use of the CI than their peers with NH. The SSD group experienced significant benefits with the CI+NH versus the NH ear alone on measures of isolated word recognition, masked sentence recognition, and localization. These benefits were realized within the first 3 months of use and were maintained through the 24-month postactivation interval. CONCLUSIONS: Young children with SSD who use a CI experience significant isolated word recognition and bilateral spatial hearing benefits, although their performance remains poorer than their peers with NH.

Cochlear Nerve Deficiency in Pediatric Unilateral Hearing Loss and Asymmetric Hearing Loss.

INTRODUCTION: The rates of cochlear nerve abnormalities and cochlear malformations in pediatric unilateral hearing loss (UHL) are conflicting in the literature, with important implications on management. The aim of this study was to investigate the incidence of cochlear nerve deficiency (CND) in pediatric subjects with UHL or asymmetric hearing loss (AHL). METHODS: A retrospective chart review of pediatric subjects <18 years of age evaluated for UHL or AHL with fine-cut heavily T2-weighted magnetic resonance imaging (MRI) between January 2014 and October 2019 (n = 291) at a tertiary referral center was conducted. MRI brain and computed tomography temporal bone were reviewed for the presence of inner ear malformations and/or CND. Status of the ipsilateral cochlear nerve and inner ear was evaluated. Pure tone average (PTA) at 500, 1,000 and 2,000 Hz was assessed. RESULTS: 204 subjects with UHL and 87 subjects with AHL were included. CND (aplasia or hypoplasia) was demonstrated in 61 pediatric subjects with UHL (29.9%) and 10 with AHL (11.5%). Ipsilateral cochlear malformations were noted in 25 subjects with UHL (12.3%) and 11 with AHL (12.6%), and ipsilateral vestibular malformations in 23 (11.3%) and 12 (13.8%) ears, respectively. Median PTA was statistically significantly higher in ears with CND (98.33) than ears with normal nerves (90.84). DISCUSSION/CONCLUSION: Imaging demonstrated a high incidence of inner ear malformations, particularly CND, in pediatric subjects with UHL. Auditory findings indicated CND cannot be ruled out by thresholds alone as some CND ears did demonstrate measurable hearing. Radiologic evaluation by MRI should be performed in all patients within this population to guide counseling and management of hearing loss based on etiology, with implications on candidacy for cochlear implantation.

Sound Source Localization by Cochlear Implant Recipients with Normal Hearing in the Contralateral Ear: Effects of Spectral Content and Duration of Listening Experience.

INTRODUCTION: Cochlear implant (CI) recipients with normal hearing (NH) in the contralateral ear experience a significant improvement in sound source localization when listening with the CI in combination with their NH-ear (CI + NH) as compared to with the NH-ear alone. The improvement in localization is primarily due to sensitivity to interaural level differences (ILDs). Sensitivity to interaural timing differences (ITDs) may be limited by auditory aging, frequency-to-place mismatches, the signal coding strategy, and duration of CI use. The present report assessed the sensitivity of ILD and ITD cues in CI + NH listeners who were recipients of long electrode arrays that provide minimal frequency-to-place mismatches and were mapped with a coding strategy that presents fine structure cues on apical channels. METHODS: Sensitivity to ILDs and ITDs for localization was assessed using broadband noise (BBN), as well as high-pass (HP) and low-pass (LP) filtered noise for adult CI + NH listeners. Stimuli were 200-ms noise bursts presented from 11 speakers spaced evenly over an 180° arc. Performance was quantified in root-mean-squared error and response patterns were analyzed to evaluate the consistency, accuracy, and side bias of the responses. Fifteen listeners completed the task at the 2-year post-activation visit; seven listeners repeated the task at a later annual visit. RESULTS: Performance at the 2-year visit was best with the BBN and HP stimuli and poorer with the LP stimulus. Responses to the BBN and HP stimuli were significantly correlated, consistent with the idea that CI + NH listeners primarily use ILD cues for localization. For the LP stimulus, some listeners responded consistently and accurately and with limited side bias, which may indicate sensitivity to ITD cues. Two of the 7 listeners who repeated the task at a later annual visit experienced a significant improvement in performance with the LP stimulus, which may indicate that sensitivity to ITD cues may improve with long-term CI use. CONCLUSIONS: CI recipients with a NH-ear primarily use ILD cues for sound source localization, though some may use ITD cues as well. Sensitivity to ITD cues may improve with long-term CI listening experience.

Influence of Postponed Follow-Up after Cochlear Implant Activation during the COVID-19 Pandemic on Aided Sound Field Detection and Speech Recognition.

INTRODUCTION: The objective of this study was to assess the influence of postponing the first post-activation follow-up due to the COVID-19 pandemic on the aided sound field detection thresholds and speech recognition of cochlear implant (CI) users. METHODS: A retrospective review was performed at a tertiary referral center. Two groups of adult CI recipients were evaluated: (1) patients whose first post-activation follow-up was postponed due to COVID-19 closures (postponed group; n = 10) and (2) a control group that attended recommended post-activation follow-ups prior to the COVID-19 pandemic (control group; n = 18). For both groups, electric thresholds were estimated at initial activation based on comfort levels and were measured behaviorally at subsequent post-activation follow-ups. For the control group, behavioral thresholds were measured at the 1-month follow-up. For the postponed group, behavioral thresholds were not measured until 3 months post-activation since the 1-month follow-up was postponed. The aided pure-tone average (PTA) and word recognition results were compared between groups at the 3-month follow-up and at an interim visit 2-9 weeks later. RESULTS: At the 3-month follow-up, the postponed group had significantly poorer word recognition (23 vs. 42%, p = 0.027) and aided PTA (42 vs. 37 dB HL, p = 0.041) than the control group. No significant differences were observed between 3-month data from the control group and interim data from the postponed group. CONCLUSIONS: The postponed follow-up after CI activation was associated with poorer outcomes, both in terms of speech recognition and aided audibility. However, these detrimental effects were reversed following provision of an individualized map, with behaviorally measured electric threshold and comfort levels. While adult CI recipients demonstrate an improvement in speech recognition with estimated electric thresholds, the present results suggest that behavioral mapping within the initial weeks of device use may support optimal outcomes.

Delaying Cochlear Implantation Impacts Postoperative Speech Perception of Nontraditional Pediatric Candidates.

INTRODUCTION: As pediatric cochlear implant (CI) candidacy expands, children with greater degrees of residual hearing are receiving CIs. These nontraditional candidates have audiometric thresholds that meet adult manufacturer labeling but are better than current pediatric guidelines allow. The purpose of this study was to determine the impact of delayed cochlear implantation on speech perception in nontraditional pediatric CI recipients. METHODS: Pediatric CI recipients with a history of progressive hearing loss and a preoperative 4-frequency pure-tone average of ≤75 dB HL at the time of implantation were considered for this retrospective study. Preoperative serial audiograms and word recognition scores were reviewed, and a method was created to establish a date when each individual ear 1st met nontraditional candidacy. The length of time between the date of candidacy and implantation was calculated and defined as the "delay time." A multiple linear regression investigated delay time, age at surgery, surgery type (1st vs. 2nd side), and array type as predictive factors of maximum postoperative Consonant-Nucleus-Consonant (CNC) word scores. A one-way ANCOVA was performed comparing the postoperative CNC scores between subjects grouped by delay time. RESULTS: A significant regression was found (F(4, 38) = 5.167, p = 0.002, R2 = 0.353). Both age at implantation (p = 0.023) and delay time (p = 0.002) predicted CNC word scores. Longer delay time was associated with poorer word recognition scores, while older age at implantation correlated with higher CNC word scores in this progressive hearing loss group. A significant difference was noted between subjects implanted with <1 year of delay and those with 3 or more years of delay (p = 0.003). All ears implanted within a year of candidacy achieved word recognition abilities that are generally accepted as above average (M = 84.91). CONCLUSION: CI candidacy for adults has evolved to allow for greater degrees of residual hearing, while audiometric guidelines for children have not changed since 2000. Our findings suggest that delay of cochlear implantation, even for children with significant levels of residual hearing, leads to poorer outcomes. Modified candidacy guidelines for children should be established to expedite referral to multidisciplinary CI teams and minimize delays in this population.

Relationship Between Electrocochleography, Angular Insertion Depth, and Cochlear Implant Speech Perception Outcomes.

OBJECTIVES: Electrocochleography (ECochG), obtained before the insertion of a cochlear implant (CI) array, provides a measure of residual cochlear function that accounts for a substantial portion of variability in postoperative speech perception outcomes in adults. It is postulated that subsequent surgical factors represent independent sources of variance in outcomes. Prior work has demonstrated a positive correlation between angular insertion depth (AID) of straight arrays and speech perception under the CI-alone condition, with an inverse relationship observed for precurved arrays. The purpose of the present study was to determine the combined effects of ECochG, AID, and array design on speech perception outcomes. DESIGN: Participants were 50 postlingually deafened adult CI recipients who received one of three straight arrays (MED-EL Flex24, MED-EL Flex28, and MED-EL Standard) and two precurved arrays (Cochlear Contour Advance and Advanced Bionics HiFocus Mid-Scala). Residual cochlear function was determined by the intraoperative ECochG total response (TR) measured before array insertion, which is the sum of magnitudes of spectral components in response to tones of different stimulus frequencies across the speech spectrum. The AID was then determined with postoperative imaging. Multiple linear regression was used to predict consonant-nucleus-consonant (CNC) word recognition in the CI-alone condition at 6 months postactivation based on AID, TR, and array design. RESULTS: Forty-one participants received a straight array and nine received a precurved array. The AID of the most apical electrode contact ranged from 341° to 696°. The TR measured by ECochG accounted for 43% of variance in speech perception outcomes (p < 0.001). A regression model predicting CNC word scores with the TR tended to underestimate the performance for precurved arrays and deeply inserted straight arrays, and to overestimate the performance for straight arrays with shallower insertions. When combined in a multivariate linear regression, the TR, AID, and array design accounted for 72% of variability in speech perception outcomes (p < 0.001). CONCLUSIONS: A model of speech perception outcomes that incorporates TR, AID, and array design represents an improvement over a model based on TR alone. The success of this model shows that peripheral factors including cochlear health and electrode placement may play a predominant role in speech perception with CIs.

Social network intervention to increase pre-exposure prophylaxis (PrEP) awareness, interest, and use among African American men who have sex with men.

In the U.S., HIV incidence is highest among Black men who have sex with men (MSM) but PrEP uptake is low, in part due to lack of normative support for using PrEP. This research pilot tested a social network-level intervention designed to increase PrEP use willingness, interest, and peer supports among Black MSM in Milwaukee. Five community social networks (n = 40 participants) of racial minority MSM were assessed at baseline with measures of PrEP knowledge, interest, attitudes, and action taking. Persons most interconnected with others in each network attended an intervention that provided training to increase knowledge about PrEPbenefits, address PrEP concerns, endorse PrEP use as a symbol of pride and health, and deliver these messages to others in their social networks. All network members were re-administered the same measures at 3-month followup. Significant increases over time were found in network members' PrEP knowledge, attitudes, norm perceptions, self-efficacy, and willingness to use PrEP. Participants more often talked with friends about HIV and with their health care providers about PrEP. The percentage of participants who reported using PrEP increased from 3% to 11%. Larger-scale evaluations of this intervention model are needed.

Frequency-to-Place Mismatch: Characterizing Variability and the Influence on Speech Perception Outcomes in Cochlear Implant Recipients.

OBJECTIVES: The spatial position of a cochlear implant (CI) electrode array affects the spectral cues provided to the recipient. Differences in cochlear size and array length lead to substantial variability in angular insertion depth (AID) across and within array types. For CI-alone users, the variability in AID results in varying degrees of frequency-to-place mismatch between the default electric frequency filters and cochlear place of stimulation. For electric-acoustic stimulation (EAS) users, default electric frequency filters also vary as a function of residual acoustic hearing in the implanted ear. The present study aimed to (1) investigate variability in AID associated with lateral wall arrays, (2) determine the subsequent frequency-to-place mismatch for CI-alone and EAS users mapped with default frequency filters, and (3) examine the relationship between early speech perception for CI-alone users and two aspects of electrode position: frequency-to-place mismatch and angular separation between neighboring contacts, a metric associated with spectral selectivity at the periphery. DESIGN: One hundred one adult CI recipients (111 ears) with MED-EL Flex24 (24 mm), Flex28 (28 mm), and FlexSOFT/Standard (31.5 mm) arrays underwent postoperative computed tomography to determine AID. A subsequent comparison was made between AID, predicted spiral ganglion place frequencies, and the default frequency filters for CI-alone (n = 84) and EAS users (n = 27). For CI-alone users with complete insertions who listened with maps fit with the default frequency filters (n = 48), frequency-to-place mismatch was quantified at 1500 Hz and angular separation between neighboring contacts was determined for electrodes in the 1 to 2 kHz region. Multiple linear regression was used to examine how frequency-to-place mismatch and angular separation of contacts influence consonant-nucleus-consonant (CNC) scores through 6 months postactivation. RESULTS: For CI recipients with complete insertions (n = 106, 95.5%), the AID (mean ± standard deviation) of the most apical contact was 428° ± 34.3° for Flex24 (n = 11), 558° ± 65.4° for Flex28 (n = 48), and 636° ± 42.9° for FlexSOFT/Standard (n = 47) arrays. For CI-alone users, default frequency filters aligned closely with the spiral ganglion map for deeply inserted lateral wall arrays. For EAS users, default frequency filters produced a range of mismatches; absolute deviations of ≤ 6 semitones occurred in only 37% of cases. Participants with shallow insertions and minimal or no residual hearing experienced the greatest mismatch. For CI-alone users, both smaller frequency-to-place mismatch and greater angular separation between contacts were associated with better CNC scores during the initial 6 months of device use. CONCLUSIONS: There is significant variability in frequency-to-place mismatch among CI-alone and EAS users with default frequency filters, even between individuals implanted with the same array. When using default frequency filters, mismatch can be minimized with longer lateral wall arrays and insertion depths that meet the edge frequency associated with residual hearing for CI-alone and EAS users, respectively. Smaller degrees of frequency-to-place mismatch and decreased peripheral masking due to more widely spaced contacts may independently support better speech perception with longer lateral wall arrays in CI-alone users.

Recommendations for Measuring the Electrically Evoked Compound Action Potential in Children With Cochlear Nerve Deficiency.

OBJECTIVES: This study reports a method for measuring the electrically evoked compound action potential (eCAP) in children with cochlear nerve deficiency (CND). DESIGN: This method was developed based on experience with 50 children with CND who were Cochlear Nucleus cochlear implant users. RESULTS: This method includes three recommended steps conducted with recommended stimulating and recording parameters: initial screen, pulse phase duration optimization, and eCAP threshold determination (i.e., identifying the lowest stimulation level that can evoke an eCAP). Compared with the manufacturer-default parameters, the recommended parameters used in this method yielded a higher success rate for measuring the eCAP in children with CND. CONCLUSIONS: The eCAP can be measured successfully in children with CND using recommended parameters. This specific method is suitable for measuring the eCAP in children with CND in clinical settings. However, it is not suitable for intraoperative eCAP recordings due to the extensive testing time required.

A non-catalytic function of carbonic anhydrase IX contributes to the glycolytic phenotype and pH regulation in human breast cancer cells.

The most aggressive and invasive tumor cells often reside in hypoxic microenvironments and rely heavily on rapid anaerobic glycolysis for energy production. This switch from oxidative phosphorylation to glycolysis, along with up-regulation of the glucose transport system, significantly increases the release of lactic acid from cells into the tumor microenvironment. Excess lactate and proton excretion exacerbate extracellular acidification to which cancer cells, but not normal cells, adapt. We have hypothesized that carbonic anhydrases (CAs) play a role in stabilizing both intracellular and extracellular pH to favor cancer progression and metastasis. Here, we show that proton efflux (acidification) using the glycolytic rate assay is dependent on both extracellular pH (pHe) and CA IX expression. Yet, isoform-selective sulfonamide-based inhibitors of CA IX did not alter proton flux, which suggests that the catalytic activity of CA IX is not necessary for this regulation. Other investigators have suggested the CA IX co-operates with the MCT transport family to excrete protons. To test this possibility, we examined the expression patterns of selected ion transporters and show that members of this family are differentially expressed within the molecular subtypes of breast cancer. The most aggressive form of breast cancer, triple-negative breast cancer, appears to co-ordinately express the monocarboxylate transporter 4 (MCT4) and carbonic anhydrase IX (CA IX). This supports a possible mechanism that utilizes the intramolecular H+ shuttle system in CA IX to facilitate proton efflux through MCT4.

MRI surveillance following concurrent cochlear implantation in cases of vestibular schwannoma resection.

OBJECTIVE: Cochlear nerve preserving translabyrinthine vestibular schwannoma (VS) resection enables concurrent cochlear implantation. Implantation in patients with VS raises important concerns including the ability to undergo postoperative magnetic resonance imaging (MRI) monitoring of residual tumor growth or tumor recurrence, specifically with a retained magnet. We aim to assess the feasibility of MRI monitoring and the impact on image quality with retained cochlear implant (CI) magnets. METHODS: Retrospective review of post-operative head MRI scans in CI recipients with a retained CI magnet, after cochlear nerve preserving translabyrinthine excision of VS. The ability to visualize the ipsilateral and contralateral internal auditory canal (IAC) and cerebellopontine angle (CPA) were assessed. RESULTS: A total of eight surveillance head MRI were performed in six patients. In one case, in which the receiver was positioned lower, the view of the ipsilateral IAC and CPA was distorted. In all other cases, the views of both the ipsilateral and contralateral IAC and CPA were overall unimpaired. DISCUSSION: Imaging artifact only very rarely impedes adequate visualization of the ipsilateral IAC or CPA in CI recipients. In anticipation of the need for further IAC and CPA imaging, it would be advisable to place the receiver in an exaggerated superior-posterior position to further decrease obscuring artifact. Thus, serial monitoring of VS tumors can be performed safely with preservation of image quality with a retained receiver magnet. CONCLUSIONS: When placing the CI receiver-stimulator farther posterior-superiorly, excellent visualization of the IAC and CPA can be accomplished without significantly impairing the image quality.

Electric-Acoustic Stimulation Outcomes in Children.

OBJECTIVES: This study investigates outcomes in children fit with electric-acoustic stimulation (EAS) and addresses three main questions: (1) Are outcomes with EAS superior to outcomes with conventional electric-only stimulation in children? (2) Do children with residual hearing benefit from EAS and conventional electric-only stimulation when compared with the preoperative hearing aid (HA) condition? (3) Can children with residual hearing derive benefit from EAS after several years of listening with conventional electric-only stimulation? DESIGN: Sixteen pediatric cochlear implant (CI) recipients between 4 and 16 years of age with an unaided low-frequency pure tone average of 75 dB HL in the implanted ear were included in two study arms. Arm 1 included new recipients, and Arm 2 included children with at least 1 year of CI experience. Using a within-subject design, participants were evaluated unilaterally with the Consonant-Nucleus-Consonant (CNC) word list in quiet and the Baby Bio at a +5 dB SNR using an EAS program and a conventional full electric (FE) program. Arm 1 participants' scores were also compared with preoperative scores. RESULTS: Speech perception outcomes were statistically higher with the EAS program than the FE program. For new recipients, scores were significantly higher with EAS than preoperative HA scores for both the CNC and Baby Bio in noise; however, after 6 months of device use, results in the FE condition were not significantly better than preoperative scores. Long-term FE users benefited from EAS over their FE programs based on CNC word scores. CONCLUSIONS: Whether newly implanted or long-term CI users, children with residual hearing after CI surgery can benefit from EAS. Cochlear implantation with EAS fitting is a viable option for children with HAs who have residual hearing but have insufficient access to high-frequency sounds and poor speech perception.

Intracochlear Electrocochleography: Response Patterns During Cochlear Implantation and Hearing Preservation.

OBJECTIVES: Electrocochleography (ECochG) obtained through a cochlear implant (CI) is increasingly being tested as an intraoperative monitor during implantation with the goal of reducing surgical trauma. Reducing trauma should aid in preserving residual hearing and improve speech perception overall. The purpose of this study was to characterize intracochlear ECochG responses throughout insertion in a range of array types and, when applicable, relate these measures to hearing preservation. The ECochG signal in cochlear implant subjects is complex, consisting of hair cell and neural generators with differing distributions depending on the etiology and history of hearing loss. Consequently, a focus was to observe and characterize response changes as an electrode advances. DESIGN: In 36 human subjects, responses to 90 dB nHL tone bursts were recorded both at the round window (RW) and then through the apical contact of the CI as the array advanced into the cochlea. The specific setup used a sterile clip in the surgical field, attached to the ground of the implant with a software-controlled short to the apical contact. The end of the clip was then connected to standard audiometric recording equipment. The stimuli were 500 Hz tone bursts at 90 dB nHL. Audiometry for cases with intended hearing preservation (12/36 subjects) was correlated with intraoperative recordings. RESULTS: Successful intracochlear recordings were obtained in 28 subjects. For the eight unsuccessful cases, the clip introduced excessive line noise, which saturated the amplifier. Among the successful subjects, the initial intracochlear response was a median 5.8 dB larger than the response at the RW. Throughout insertion, modiolar arrays showed median response drops after stylet removal while in lateral wall arrays the maximal median response magnitude was typically at the deepest insertion depth. Four main patterns of response magnitude were seen: increases > 5 dB (12/28), steady responses within 5 dB (4/28), drops > 5 dB (from the initial response) at shallow insertion depths (< 15 mm deep, 7/28), or drops > 5 dB occurring at deeper depths (5/28). Hearing preservation, defined as < 80 dB threshold at 250 Hz, was successful in 9/12 subjects. In these subjects, an intracochlear loss of response magnitude afforded a prediction model with poor sensitivity and specificity, which improved when phase, latency, and proportion of neural components was considered. The change in hearing thresholds across cases was significantly correlated with various measures of the absolute magnitudes of response, including RW response, starting response, maximal response, and final responses (p's < 0.05, minimum of 0.0001 for the maximal response, r's > 0.57, maximum of 0.80 for the maximal response). CONCLUSIONS: Monitoring the cochlea with intracochlear ECochG during cochlear implantation is feasible, and patterns of response vary by device type. Changes in magnitude alone did not account for hearing preservation rates, but considerations of phase, latency, and neural contribution can help to interpret the changes seen and improve sensitivity and specificity. The correlation between the absolute magnitude obtained either before or during insertion of the ECochG and the hearing threshold changes suggest that cochlear health, which varies by subject, plays an important role.

Response Changes During Insertion of a Cochlear Implant Using Extracochlear Electrocochleography.

OBJECTIVES: Electrocochleography is increasingly being utilized as an intraoperative monitor of cochlear function during cochlear implantation (CI). Intracochlear recordings from the advancing electrode can be obtained through the device by on-board capabilities. However, such recordings may not be ideal as a monitor because the recording electrode moves in relation to the neural and hair cell generators producing the responses. The purposes of this study were to compare two extracochlear recording locations in terms of signal strength and feasibility as intraoperative monitoring sites and to characterize changes in cochlear physiology during CI insertion. DESIGN: In 83 human subjects, responses to 90 dB nHL tone bursts were recorded both at the round window (RW) and then at an extracochlear position-either adjacent to the stapes or on the promontory just superior to the RW. Recording from the fixed, extracochlear position continued during insertion of the CI in 63 cases. RESULTS: Before CI insertion, responses to low-frequency tones at the RW were roughly 6 dB larger than when recording at either extracochlear site, but the two extracochlear sites did not differ from one another. During CI insertion, response losses from the promontory or adjacent to the stapes stayed within 5 dB in ≈61% (38/63) of cases, presumably indicating atraumatic insertions. Among responses which dropped more than 5 dB at any time during CI insertion, 12 subjects showed no response recovery, while in 13, the drop was followed by partial or complete response recovery by the end of CI insertion. In cases with recovery, the drop in response occurred relatively early (<15 mm insertion) compared to those where there was no recovery. Changes in response phase during the insertion occurred in some cases; these may indicate a change in the distributions of generators contributing to the response. CONCLUSIONS: Monitoring the electrocochleography during CI insertion from an extracochlear site reveals insertions that are potentially atraumatic, show interaction with cochlear structures followed by response recovery, or show interactions such that response losses persist to the end of recording.

The Breast Cancer Tumor Suppressor TRIM29 Is Expressed via ATM-dependent Signaling in Response to Hypoxia.

Reduced ATM function has been linked to breast cancer risk, and the TRIM29 protein is an emerging breast cancer tumor suppressor. Here we show that, in cultured breast tumor and non-tumorigenic mammary epithelial cells, TRIM29 is up-regulated in response to hypoxic stress but not DNA damage. Hypoxia-induced up-regulation of TRIM29 is dependent upon ATM and HIF1α and occurs through increased transcription of the TRIM29 gene. Basal expression of TRIM29 is also down-regulated in cells expressing diminished levels of ATM, and findings suggest that this occurs through basal NF-κB activity as knockdown of the NF-κB subunit RelA suppresses TRIM29 abundance. We have previously shown that the activity of the TWIST1 oncogene is antagonized by TRIM29 and now show that TRIM29 is necessary to block the up-regulation of TWIST1 that occurs in response to hypoxic stress. This study establishes TRIM29 as a hypoxia-induced tumor suppressor gene and provides a novel molecular mechanism for ATM-dependent breast cancer suppression.

ATM is required for SOD2 expression and homeostasis within the mammary gland.

PURPOSE: ATM activates the NF-κB transcriptional complex in response to genotoxic and oxidative stress. The purpose of this study was to examine if the NF-κB target gene and critical antioxidant SOD2 (MnSOD) in cultured mammary epithelium is also ATM-dependent, and what phenotypes arise from deletion of ATM and SOD2 within the mammary gland. METHODS: SOD2 expression was studied in human mammary epithelial cells and MCF10A using RNAi to knockdown ATM or the NF-κB subunit RelA. To study ATM and SOD2 function in mammary glands, mouse lines containing Atm or Sod2 genes containing LoxP sites were mated with mice harboring Cre recombinase under the control of the whey acidic protein promoter. Quantitative PCR was used to measure gene expression, and mammary gland structure was studied using histology. RESULTS: SOD2 expression is ATM- and RelA-dependent, ATM knockdown renders cells sensitive to pro-oxidant exposure, and SOD mimetics partially rescue this sensitivity. Mice with germline deletion of Atm fail to develop mature mammary glands, but using a conditional knockout approach, we determined that Atm deletion significantly diminished the expression of Sod2. We also observed that these mice (termed AtmΔ/Δ) displayed a progressive lactation defect as judged by reduced pup growth rate, aberrant lobulo-alveolar structure, diminished milk protein gene expression, and increased apoptosis within lactating glands. This phenotype appears to be linked to dysregulated Sod2 expression as mammary gland-specific deletion of Sod2 phenocopies defects observed in AtmΔ/Δ dams. CONCLUSIONS: We conclude that ATM is required to promote expression of SOD2 within the mammary epithelium, and that both ATM and SOD2 play a crucial role in mammary gland homeostasis.

PKR inhibits the DNA damage response, and is associated with poor survival in AML and accelerated leukemia in NHD13 mice.

Increased expression of the interferon-inducible double-stranded RNA-activated protein kinase (PKR) has been reported in acute leukemia and solid tumors, but the role of PKR has been unclear. Now, our results indicate that high PKR expression in CD34(+) cells of acute myeloid leukemia (AML) patients correlates with worse survival and shortened remission duration. Significantly, we find that PKR has a novel and previously unrecognized nuclear function to inhibit DNA damage response signaling and double-strand break repair. Nuclear PKR antagonizes ataxia-telangiectasia mutated (ATM) activation by a mechanism dependent on protein phosphatase 2A activity. Thus, inhibition of PKR expression or activity promotes ATM activation, γ-H2AX formation, and phosphorylation of NBS1 following ionizing irradiation. PKR transgenic but not PKR null mice demonstrate a mutator phenotype characterized by radiation-induced and age-associated genomic instability that was partially reversed by short-term pharmacologic PKR inhibition. Furthermore, the age-associated accumulation of somatic mutations that occurs in the Nup98-HOXD13 (NHD13) mouse model of leukemia progression was significantly elevated by co-expression of a PKR transgene, whereas knockout of PKR expression or pharmacologic inhibition of PKR activity reduced the frequency of spontaneous mutations in vivo. Thus, PKR cooperated with the NHD13 transgene to accelerate leukemia progression and shorten survival. Taken together, these results indicate that increased nuclear PKR has an oncogenic function that promotes the accumulation of potentially deleterious mutations. Thus, PKR inhibition may be a therapeutically useful strategy to prevent leukemia progression or relapse, and improve clinical outcomes.

Effect of Cochlear Implantation on Quality of Life in Adults with Unilateral Hearing Loss.

OBJECTIVE: Patients with moderate-to-profound sensorineural hearing loss in 1 ear and normal hearing in the contralateral ear, known as unilateral hearing loss (UHL) or single-sided deafness (SSD), may experience improved quality of life with the use of a cochlear implant (CI) in the affected ear. Quality of life assessment before and after implantation may reveal changes to aspects of hearing beyond those explicitly evaluated with behavioral measures. METHODS: The present report completed 2 experiments investigating quality of life outcomes in CI recipients with UHL. The first experiment assessed quality of life during the 1st year of device use with 3 questionnaires: the Speech, Spatial, and Qualities of Hearing Scale (SSQ), the Abbreviated Profile of Hearing Aid Benefit (APHAB), and the Tinnitus Handicap Inventory. Twenty subjects were evaluated preoperatively and 1, 3, 6, 9, and 12 months post-activation. Quality of life results were compared over the study period using traditional scoring methods and the SSQ pragmatic subscales. Subscales specific to localization and speech perception in noise were compared to behavioral measures at the preoperative and 12-month intervals. The 2nd experiment evaluated quality of life preoperatively and at the 12-month interval for CI recipients with UHL and CI recipients with bilateral hearing loss, including conventional CI users and those listening with electric-acoustic stimulation (EAS). The 3 cohorts differed in CI candidacy criteria, including the amount of residual hearing in the contralateral ear. RESULTS: For subjects with moderate-to-profound UHL, receipt of a CI significantly improved quality of life, with benefits noted as early as 1 month after initial activation. The UHL cohort reported less perceived difficulty at the pre- and postoperative intervals than the conventional CI and EAS cohorts, which may be due to the presence of the normal-hearing ear. Each group experienced a significant benefit in quality of life on the APHAB with CI use. CONCLUSIONS: Cochlear implantation in cases of substantial UHL may offer significant improvements in quality of life. Quality of life measures revealed a reduction in perceived tinnitus severity and subjective improvements in speech perception in noise, spatial hearing, and listening effort. While self-report of difficulties were lower for the UHL cohort than the conventional CI and EAS cohorts, subjects in all 3 groups reported an improvement in quality of life with CI use.

Cochlear Implantation in Cases of Unilateral Hearing Loss: Initial Localization Abilities.

OBJECTIVES: The present study evaluated early auditory localization abilities of cochlear implant (CI) recipients with normal or near-normal hearing (NH) in the contralateral ear. The goal of the study was to better understand the effect of CI listening experience on localization in this population. DESIGN: Twenty participants with unilateral hearing loss enrolled in a prospective clinical trial assessing outcomes of cochlear implantation (ClinicalTrials.gov Identifier: NCT02203305). All participants received the MED-EL Standard electrode array, were fit with an ear-level audio processor, and listened with the FS4 coding strategy. Localization was assessed in the sound field using an 11-speaker array with speakers uniformly positioned on a horizontal, semicircular frame. Stimuli were 200-msec speech-shaped noise bursts. The intensity level (52, 62, and 72 dB SPL) and sound source were randomly interleaved across trials. Participants were tested preoperatively, and 1, 3, and 6 months after activation of the audio processor. Performance was evaluated in two conditions at each interval: (1) unaided (NH ear alone [NH-alone] condition), and (2) aided, with either a bone conduction hearing aid (preoperative interval; bone conduction hearing aid + NH condition) or a CI (postoperative intervals; CI + NH condition). Performance was evaluated by comparing root-mean-squared (RMS) error between listening conditions and between measurement intervals. RESULTS: Mean RMS error for the soft, medium, and loud levels were 66°, 64°, and 69° in the NH-alone condition and 72°, 66°, and 70° in the bone conduction hearing aid + NH condition. Participants experienced a significant improvement in localization in the CI + NH condition at the 1-month interval (38°, 35°, and 38°) as compared with the preoperative NH-alone condition. Localization in the CI + NH condition continued to improve through the 6-month interval. Mean RMS errors were 28°, 25°, and 28° in the CI + NH condition at the 6-month interval. CONCLUSIONS: Adult CI recipients with normal or near-normal hearing in the contralateral ear experienced significant improvement in localization after 1 month of device use, and continued to improve through the 6-month interval. The present results show that binaural acclimatization in CI users with unilateral hearing loss can progress rapidly, with marked improvements in performance observed after only 1 month of listening experience.